PHARMACOKINETICS AND PHARMACODYNAMICS OF 24-HOURLY KAPANOL COMPARED TO 12-HOURLY MS CONTIN IN THE TREATMENT OF SEVERE CANCER PAIN

Twenty-four patients with severe pain related to cancer completed a ra ndomised, double-blind, double-dummy, crossover study examining morphi ne pharmacokinetics and pharmacodynamics when the same 24-h morphine d ose was administered using two modified release oral morphine formulat ions; either one dose of Kapanol(TM) (a new sustained release polymer coated pellet formulation administered in capsule form, Glaxo Wellcome group of companies) per 24 h, or MS Contin(R) (Purdue Frederick Compa ny, Connecticut, USA) administered at 12-h intervals. The morphine dos e was optimised for each patient using an immediate release morphine s olution in the lead-in period to provide the most favourable balance b etween pain relief and side-effects. Patients were then randomly alloc ated to receive their 24-h morphine dose as either Kapanol or MS Conti n in period 1. Patients recorded daily measures of pain relief and mor phine related side-effects (morphine pharmacodynamics) in a diary. Pat ients were admitted to the Pain Management Unit on the morning of day 7 (+/-1 day) and frequent blood samples were collected for 24 h follow ing the 10:00 h dose to fully characterise the pharmacokinetic profile for morphine and its metabolites at steady state. Morphine pharmacody namics and the amount and timing of rescue medication (dextromoramide) were also recorded during this time. Period 2, which commenced at 10: 00 h on day 8, was identical to period 1 except the modified release f ormulations were changed. The pharmacokinetic profile of Kapanol exhib ited a significantly higher C-min (minimum plasma morphine concentrati on), less fluctuation in plasma morphine concentration throughout the dosing interval, a longer T-max (time associated with the maximum morp hine concentration) and a greater time that the plasma morphine concen tration was greater than or equal to 75% of C-max (an index of the con trol the formulation exerts over the morphine release rate) compared t o that of MS Contin. Some of these pharmacokinetic differences (e.g., C-min and fluctuation in plasma morphine concentration) were surprisin g given that the dosing interval for Kapanol (24 h) was double that of MS Contin (12 h). There was no significant difference between the Kap anol and MS Contin treatment phases in any of the pharmacodynamic para meters, morphine related side-effects, the percentage of patients taki ng rescue medication as well as the amount or time to the first dose o f rescue analgesia on day 7 in periods 1 and 2, patient or investigato r assessments of global efficacy at the end of periods 1 and 2, or pat ient treatment preference at the end of the study. Once a day Kapanol provided the same degree of pain relief and morphine related side-effe cts as 12-h MS Contin.